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Published on: July 21, 2018
FAK-targeting PROTAC demonstrates enhanced antitumor activity against KRAS mutant non-small cell lung cancer
Jinyuan Liu1, Lei Xue1, Xiang Xu2
1Department of Thoracic Surgery, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
Abstract:
Focal adhesion kinase (FAK) has been established as a promising therapeutic target for KRAS mutant non-small cell lung cancer (NSCLC). However, phase II clinical trials of a FAK inhibitor (Defactinib) have only shown modest antitumor activity. To address this challenge, here we report the use of a FAK-targeting proteolysis targeting chimera (D-PROTAC) to treat KRAS mutant NSCLC. We validated that D-PROTAC could efficiently eliminate FAK protein via the ubiquitin-proteasome pathway in KRAS mutant NSCLC A427 cells, causing over 90% degradation at 800 nM. After comparing both in vitro and in vivo therapeutic efficacies, we demonstrated that D-PRTOAC outperformed Defactinib in inhibiting tumor growth. Specifically, D-PROTAC at 800 nM reduced cell viability, migration, and invasion by ∼80%. Furthermore, a ∼85% suppression of tumor growth was elicited by D-PROTAC when intratumorally administrated at 10 mg/kg in subcutaneous A427-bearing mice. These results thus demonstrate for the first time that PROTACs may serve as promising therapeutic agents for the intractable NSCLC harboring KRAS mutations.
Insights
A novel proteolysis targeting chimera (PROTAC) effectively degrades focal adhesion kinase (FAK) protein in KRAS mutant non-small cell lung cancer (NSCLC) cells. This D-PROTAC demonstrated superior efficacy over traditional inhibitors in preclinical models of NSCLC.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Focal adhesion kinase (FAK) is a therapeutic target for KRAS-mutant non-small cell lung cancer (NSCLC).
- Existing FAK inhibitors like Defactinib show limited efficacy in clinical trials for NSCLC.
- There is a need for more effective therapeutic strategies for KRAS-mutant NSCLC.
Purpose of the Study:
- To develop and evaluate a FAK-targeting proteolysis targeting chimera (D-PROTAC) for KRAS-mutant NSCLC.
- To compare the therapeutic efficacy of D-PROTAC with Defactinib in vitro and in vivo.
- To establish PROTACs as potential therapeutic agents for KRAS-mutant NSCLC.
Main Methods:
- Utilized a FAK-targeting proteolysis targeting chimera (D-PROTAC) in KRAS-mutant NSCLC A427 cells.
- Validated FAK protein degradation via the ubiquitin-proteasome pathway.
- Assessed in vitro effects on cell viability, migration, and invasion.
- Evaluated in vivo tumor growth suppression in a subcutaneous mouse model.
Main Results:
- D-PROTAC achieved over 90% FAK protein degradation at 800 nM in A427 cells.
- D-PROTAC significantly reduced cell viability, migration, and invasion by approximately 80% at 800 nM.
- Intratumoral administration of D-PROTAC (10 mg/kg) suppressed tumor growth by approximately 85% in mice.
- D-PROTAC demonstrated superior antitumor activity compared to Defactinib.
Conclusions:
- PROTAC technology offers a promising therapeutic approach for KRAS-mutant NSCLC.
- D-PROTAC effectively degrades FAK and inhibits tumor progression in preclinical NSCLC models.
- This study highlights the potential of D-PROTAC as a novel treatment for intractable NSCLC.
